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EP3508492A1 - Dérivés de tiacumicine et leur utilisation en tant qu'antibiotiques - Google Patents

Dérivés de tiacumicine et leur utilisation en tant qu'antibiotiques Download PDF

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Publication number
EP3508492A1
EP3508492A1 EP18150671.8A EP18150671A EP3508492A1 EP 3508492 A1 EP3508492 A1 EP 3508492A1 EP 18150671 A EP18150671 A EP 18150671A EP 3508492 A1 EP3508492 A1 EP 3508492A1
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Prior art keywords
independently
alkyl
mmol
compound according
compound
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EP18150671.8A
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German (de)
English (en)
Inventor
Karl Gademann
Regina Berg
Andrea Meier
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Zurich Universitaet Institut fuer Medizinische Virologie
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Zurich Universitaet Institut fuer Medizinische Virologie
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Priority to EP18150671.8A priority Critical patent/EP3508492A1/fr
Priority to PCT/EP2019/050353 priority patent/WO2019135010A1/fr
Publication of EP3508492A1 publication Critical patent/EP3508492A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

  • the present invention relates to novel macrolide compounds and their use as antibiotics.
  • Fidaxomicin has been reported to show antibacterial activity against gram-positive bacteria in the micromolar range and has been approved as a drug for the treatment of Clostridium difficile -associated diarrhea.
  • fidaxomicin A limitation of the members of the tiacumicin family including fidaxomicin, are their poor pharmacokinetic properties. As fidaxomicin is not systemically absorbed, it can only serve as a topical treatment for Clostridium difficile infections in the gut. Thus, the high antibacterial potential of tiacumicin antibiotics against a wide variety of pathogenic bacteria has not been exploited yet. Derivative compounds with an improved pharmacokinetic profile, in particular with an improved solubility and absorbability, would allow for systemic administration of the drug and could be used for a much wider variety of infections. Facing an enormous spread of resistant bacterial strains, a generation of semisynthetically modified tiacumicins could be used as drugs of last resort for treatment of problematic infections such as tuberculosis.
  • the objective of the present invention is to provide derivatives of tiacumicin compounds with an improved pharmacokinetic profile to be used in the treatment of bacterial infections. This objective is attained by the claims of the present specification.
  • a compound characterized by a general formula (1) is provided.
  • the linker L may be a linear or branched alkyl, in particular a linear alkyl. If n and t are both 1, both linker L may be a linear alkyl, both may be a branched alkyl or one L may be a linear alkyl and the other L may be a branched alkyl.
  • L is selected from C 1-12 alkyl, in particular C 1-6 -alkyl, more particularly C 1-3 -alkyl.
  • the residue R 5 contributes to an improved pharmacokinetic of the compounds according to the invention in comparison to fidaxomicin itself.
  • the compounds according to the invention are effective against bacteria such as Mycobacterium tuberculosis. Furthermore, the compounds according to the invention show an increased solubility compared to fidaxomicin.
  • the polylinker R d may comprise a mix of linear and branched, only linear or only branched - alkyl-O- moieties, in particular only linkear alkyl-O- moieties, wherein u may be the same for all elements or different for all or some elements.
  • the polylinker R d may comprise several identical elements, for example five -(CH 2 ) 2 -O-moieties. In this case, m equals 5 and u for each element is 2.
  • the polylinker R d may comprise several different elements, for example one -CH 2 -O- moiety and four -(CH 2 ) 2 -O- moieties.
  • m equals 5 and u is 1 for the first element and u is 2 for the second to fifth element.
  • the elements that form the polyether linker R d are selected from - CH 2 -O-, -(CH 2 ) 2 -O-, -(CH 2 ) 3 -O-, -(CH 2 ) 4 -O-, -isopropyl-O-, - tert -butyl-O-, -isobutyl-O- or - sec- butyl-O-.
  • the elements that form the polyether linker R d are selected from CH 2 -O-, -(CH 2 ) 2 -O-, -(CH 2 ) 3 -O- or -(CH 2 ) 4 -O-, in particular CH 2 -O-, -(CH 2 ) 2 -O- or -(CH 2 ) 3 -O-, more particularly CH 2 -O- or -(CH 2 ) 2 -O-.
  • the compounds according to the present invention may be fidaxomicin derivatives coupled to a dye.
  • Such compounds are for example useful for studying cellular uptake, localization or distribution in a biological assay or model system or in a living organism.
  • R e is a fluorescent dye, in particular fluorescein.
  • the compounds according to the present invention may be fidaxomicin derivatives coupled to an antibiotic. Such compounds may be effective against a broader variety of bacteria compared to fidaxomicin or the other antibiotic alone. Moreover, the solubility of such compounds compared to the solubility of fidaxomicin may be enhanced.
  • R e is an antibiotic, in particular rifampicin or ciprofloxacin.
  • R e is a fluorescent dye or an antibiotic, in particular flurorescein, rifampicin or ciprofloxacin.
  • substituted refers to the addition of a substituent group to a parent compound.
  • Substituent groups can be protected or unprotected and can be added to one available site or to many available sites in a parent compound. Substituent groups may also be further substituted with other substituent groups and may be attached directly or by a linking group such as an alkyl or hydrocarbyl group to a parent compound.
  • each R ⁇ , R ⁇ and R ⁇ is, independently, H or a further substituent group with a preferred list including without limitation, H, alkyl, alkenyl, alkynyl, aliphatic, alkoxy, acyl, aryl, heteroaryl, alicyclic, heterocyclic and heteroarylalkyl.
  • a C 1 -C 6 alkyl in the context of the present invention signifies a saturated linear or branched hydrocarbon having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • Non-limiting examples for a C 1 -C 6 alkyl include methyl, ethyl, propyl, butyl, isopropyl, n-hexyl, 3-methylbut-2-enyl, 2-methylbut-3-enyl, 3-methylbut-3-enyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1,2-dimethylpropyl, pent-4-inyl, 3-methyl-2-pentyl, and 4-methyl-2-pentyl.
  • a cyclic alkyl in the context of the present invention signifies a cyclic saturated hydrocarbon such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • alkenyl in the context of the present invention refers to a straight or branched hydrocarbon chain moiety containing up to 10 carbon atoms and having at least one carbon-carbon double bond.
  • alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, dienes such as 1,3-butadiene and the like.
  • Alkenyl groups typically include from 2 to about 10 carbon atoms, more typically from 2 to about 6 carbon atoms. Alkenyl groups as used herein may optionally include further substituent groups.
  • alkynyl in the context of the present invention refers to a straight or branched hydrocarbon moiety containing up to 10 carbon atoms and having at least one carbon-carbon triple bond.
  • alkynyl groups include, without limitation, ethynyl, 1-propynyl, 1-butynyl, and the like.
  • Alkynyl groups typically include from 2 to about 10 carbon atoms, more typically from 2 to about 6 carbon atoms. Alkynyl groups as used herein may optionally include further substituent groups.
  • alcohol in the context of the present invention refers to a hydroxyl-substituted alkyl moiety.
  • a C 6 -alcohol signifies a hydroxyl-substituted C 6 -alkyl such as -(CH 2 ) 6 -OH.
  • Non-limiting examples of hydroxy-substituted alkyl include -CH 2 OH, -(CH 2 ) 2 OH, -(CH 2 ) 3 OH, - CH 2 CH(OH)CH 3 , -(CH 2 ) 4 OH, -CH(CH 2 OH)CH 2 CH 3 , -CH 2 CH(CH 2 OH)CH 3 , - CH(OH)(CH 2 ) 2 OH, -CH 2 CH(OH)CH 2 OH, -CH 2 CH(OH)(CH 2 ) 2 OH and -CH 2 CH(CH 2 OH) 2 .
  • silyl ether in the context of the present invention refers to a -O-Si-R x R y R z moiety, wherein R x , R y and R z are independently from each other selected from linear or branched C 1-6 -alkyl, C 4-8 -cyclo-alkyl or phenyl,
  • Non limiting examples of silyl ether include trimethylsilyl ether, triethylsilyl ether, tert -butyldimethylsilyl ether, tert -butyldiphenylsilyl ether and triisopropylsilyl ether.
  • ciprofloxacin in the context of the present invention signifies the antibiotic compound 1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-quinoline-3-carboxylic acid ( CAS 85721-33-1 ).
  • rifampicin in the context of the present invention signifies the antibiotic compound (7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-26- ⁇ (E)-[(4-methylpiperazin-1-yl)imino]methyl ⁇ -6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(28),2,4,9,19,21,25(29), 26-octaen-13-yl acetate ( CAS 13292-46-1 ).
  • fluorescein in the context of the present invention signifies the antibiotic compound 3',6'-dihydroxyspiro[isobenzofuran-1(3 H ),9'-[9 H ]xanthen]-3-one ( CAS 2321-07-5 ).
  • fidaxomicin in the context of the present invention signifies the antibiotic compound 3-(((6-Deoxy-4- O -(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2- O -methyl- ⁇ -D-mannopyranosyl)oxy)-methyl)-12( R )-[(6-deoxy-5- C -methyl-4- O -(2-methyl-1-oxopropyl)- ⁇ -D-lyxo-hexopyranosyl)oxy]-11( S )-ethyl-8( S )-hydroxy-18( S )-(1(R)-hydroxyethyl)-9,13,15-trimethyloxacyclooctadeca-3,5,9,13,15-pentaene-2-one ( CAS 873857-62-6 ).
  • aryl in the context of the present invention signifies a cyclic aromatic C 5 -C 10 hydrocarbon.
  • aryl include, without being restricted to, phenyl, naphthyl and heteroaryl.
  • a heteroaryl in the context of the present invention is an aryl that comprises one or several nitrogen, oxygen and/or sulphur atoms.
  • heteroaryl include, without being restricted to, pyrrole, thiophene, furan, imidazole, pyrazole, thiazole, oxazole, pyridine, pyrimidine, thiazin, quinoline, benzofuran and indole.
  • An aryl or a heteroaryl in the context of the invention additionally may be substituted by one or more alkyl groups.
  • the compound is characterized by general formula (2), with R 5' and R 5'' having independently from each other the same meaning as defined for R 5 and R 1 ,R 2 , R 3 , R 4 , R 5 and X having the same meaning as defined above.
  • R 5 and R 5'' are independently from each other -OH, -O-L-R a -R e , -OR e , -O-L-R a -R b -R e , -O-L-R a -R b -R a -R e , -O-L-R e , -O-L-R b -R b -R e , -O-L-R b -R e , -O-L-R b -L-R a -R e , - O-L-R b -L-R b -R e , -O-R d -R e , -O-L-R b -R d -L-R e , -O-R d -L-R e , or -O-R d -L-R b -
  • R 5' and R 5'' are independently from each other -OH, -O-L-R a -R e , - O-L-R a -R b -R e , -O-L-R a -R b -R a -R e , -O-L-R e , -O-L-R b -R b -R e , -O-L-R b -R e , -O-L-R b -L-R a -R e , -O-L-R b -L-R b -R e , -O-R d -R e , -O-L-R b -R d -L-R e , -O-R d -L-R e , or -O-R d -L-R b -R e .
  • R 5' and R 5'' are independently from each other -OH, -O-L-R a -R e , -O-L-R a -R b -R e , -O-L-R a -R b -R a -R e , -O-L-R e , -O-L-R a -R e , -O-L-R b -R b -R e , -O-L-R b -R e , -O-L-R b -R e , -O-L-R b -L-R b -R e , -O-R d -R e , -O-L-R b -R d -L-R e , or -O-R d -L-R e .
  • R 5' and R 5'' are independently from each other -OH, -O-L-R a -R b -R e , -O-L-R a -R b -R a -R e , -O-L-R e , -O-L-R a -R e , -O-L-R b -R b -R e , -O-L-R b -R e , -O-L-R b -L-R b -R e , -O-R d -R e , -O-L-R b -R d L-R e , or -O-R d L-R e .
  • R 5' and R 5'' are independently from each other -OH, -O-L-R a -R b -R e , -O-L-R b -L-R b -R e , -O-R d -R e , -O-L-R b -R d -L-R e -O-L-R a -R b -R a -R e , -O-L-R b -R b -R e , or -O-R d -L-R e .
  • R 5' and R 5'' are independently from each other -OH, -O-L-R a -R b -R e , -O-L-R b -L-R b -R e , -O-R d -R e , or -O-L-R b -R d -L-R e .
  • R 5' and R 5'' are independently from each other -OH, -O-L-R a -R e , -O-L-R b -L-R b -R e , or -O-R d -L-R b -R e .
  • one of R 5' and R 5" is selected from -O-L-R a -R e , -OR e , -O-L-R a -R b -R e , -O-L-R a -R b -R a -R e , -O-L-R e , -O-L-R b -R b -R e , -O-L-R b -R e , -O-L-R b -L-R a -R e , - O-L-R b -L-R b -R e , -O-R d -R e , -O-L-R b -R d -L-R e , -O-R d -L-R e , or -O-R d -L-L-L-R e , or -O
  • one of R 5' and R 5" is selected from -O-L-R a -R e , -O-L-R a -R b -R e , -O-L-R a -R b -R a -R e , -O-L-R e , -O-L-R b -R b -R e , -O-L-R b -R e , -O-L-R b -L-R a -R e , -O-L-R b -L-R b -R e , -O-R d -R e , -O-L-R b -R d -L-R e , -O-R d -L-R e , or -O-R d -L-R b -R
  • one of R 5' and R 5" is selected from -O-L-R a -R e , -O-L-R a -R b -R e , -O-L-R a -R b -R a -R e , -O-L-R e , -O-L-R a -R e , -O-L-R b -R b -R e , -O-L-R b -R e , -O-L-R b -R e , -O-L-R b -L-R b -R e , -O-R d -R e , -O-L-R b -R d -L-R e , or -O-R d -L-R e and the other one of R 5' and R 5" , in particular R 5" , is -
  • one of R 5' and R 5" is selected from -O-L-R a -R b -R e , - O-L-R a -R b -R a -R e , -O-L-R e , -O-L-R a -R e , -O-L-R b -R b -R e , -O-L-R b -R e , -O-L-R b -L-R b -R e , -O-R d -R e , -O-L-R b -R d -L-R e , or -O-R d -L-R e and the other one of R 5' and R 5" , in particular R 5" , is -OH or both R 5' and R 5'' are independently from each other selected from
  • one of R 5' and R 5" is selected from -O-L-R a -R b -R e , - O-L-R b -L-R b -R e , -O-R d -R e , -O-L-R b -R d -L-R e , -O-L-R a -R b -R a -R e , -O-L-R b -R b -R e , or -O-R d -L-R e and the other one of R 5' and R 5" , in particular R 5" , is -OH or both R 5' and R 5" are independently from each other selected from -O-L-R a -R b -R e , -O-L-R b -L-R b -R e ,
  • one of R 5' and R 5" is selected from -O-L-R a -R b -R e , - O-L-R b -L-R b -R e , -O-R d -R e , or -O-L-R b -R d -L-R e and the other one of R 5' and R 5" , in particular R 5" , is -OH or both R 5' and R 5'' are independently from each other selected from -O-L-R a -R b -R e , -O-L-R b -L-R b -R e , -O-R d -R e , or -O-L-R b -R d -L-R e , in particular one of R 5' and R 5" , in particular R 5' , is selected from -O-L-R a -R b
  • one of R 5' and R 5" is selected from -O-L-R a -R e , -O-L-R b -L-R b -R e , or -O-R d -L-R b -R e and the other one of R 5' and R 5" , in particular R 5" , is -OH or both R 5' and R 5'' are independently from each other selected from -O-L-R a -R e , -O-L-R b -L-R b -R e , or -O-R d -L-R b -R e , in particular one of R 5' and R 5" , in particular R 5' , is selected from -O-L-R a -R e , -O-L-R b -L-R b -R e , or -O-O-L-R a -R e
  • R 1 and R 2 are -OH.
  • R 3 and R 4 are independently from each other -OH or -O-(CH 2 ) 1-4 -CH 3 .
  • R 3 and R 4 are independently from each other -OH, -O-CH 2 -CH 3 or - OCH 3 .
  • R 3 and R 4 are -OH.
  • L is C 1-6 -alkyl.
  • L is C 1-3 -alkyl.
  • R b of R 5 is a five to six membered heterocycle, a C 5-6 -cycloalkyl or C 6 -aryl.
  • R b of R 5 is a five to six membered heterocycle or C 6 -aryl.
  • R b of R 5 is independently selected from piperazine, piperidine, tetrazole, triazole, imidiazole or phenyl.
  • R b of R 5 is a five to six membered heterocycle.
  • R b of R 5 is independently selected from piperazine, piperidine, tetrazole, triazole or imidiazole
  • R b of R 5 is independently selected from piperazine, piperidine or triazole.
  • R e of R 5 is -H, -C 1-2 -alkyl, -C 2-4 -alkenyl, allyl, -OH, -COOH, -NH 2 , -N 3 , -SO 2 F, ciprofloxacin, fluorescein or rifampicin.
  • R e of R 5 is -H, C 1-2 -alkyl, -OH, -COOH, -NH 2 , -N 3 or -SO 2 F.
  • R e of R 5 is -H, C 1-2 -alkyl, -OH, -COOH or -NH 2 .
  • m is 4 to 8.
  • m is 5 to 7.
  • the elements of R d are independently selected from -(CH 2 ) 1-4 -O-.
  • the elements of R d are independently selected from -(CH 2 ) 1-2 -O-.
  • the first element of R d is -CH 2 -O- and the other elements of R d are - (CH 2 ) 2 -O-.
  • m is 4 to 8 and the elements of R d are independently selected from - (CH 2 ) 1-4 -O-.
  • m is 4 to 8 and the elements of R d are independently selected from - (CH 2 ) 1-2 -O-.
  • m is 4 to 8 and each element of R d -(CH 2 ) 2 -O-.
  • m is 4 to 8 and the first element of R d is -CH 2 -O- and the other elements of R d are -(CH 2 ) 2 -O-.
  • m is 5 to 7 and the elements of R d are independently selected from - (CH 2 ) 1-4 -O-.
  • m is 5 to 7 and the elements of R d are independently selected from - (CH 2 ) 1-2 -O-.
  • m is 5 to 7 and each element of R d -(CH 2 ) 2 -O-.
  • m is 5 to 7 and the first element of R d is -CH 2 -O- and the other elements of R d are -(CH 2 ) 2 -O-.
  • z of X z is 1 or 2 and each X z is independently from each other X z - CF 3 , -O-CF 3 , -S-CF 3 , -SO-CF 3 , -SO 2 CF 3 , SO 2 -NH-CF 3 , -F, -Cl, -Br or -I.
  • z of X z is 1 or 2 and each X z is independently from each other X z -F, -Cl, -Br or -I.
  • z of X z is 1 or 2 and X z is -Cl.
  • z of X z is 2 and each X z is independently from each other X z -CF 3 , - O-CF 3 , -S-CF 3 , -SO-CF 3 , -SO 2 CF 3 , SO 2 -NH-CF 3 , -F, -Cl, -Br or -I.
  • z of X z is 2 and each X z is independently from each other X z -F, -Cl, -Br or -I.
  • z of X z is 2 and X z is -Cl.
  • one of R 5' and R 5" is selected from -O-L-R a -R e , -OR e , -O-L-R a -R b -R e , -O-L-R a -R b -R a -R e , -O-L-R e , -O-L-R b -R b -R e , -O-L-R b -R e , -O-L-R b -L-R a -R e , - O-L-R b -L-R b -R e , -O-R d -R e , -O-L-R b -R d -L-R e , -O-R d -L-R e , or -O-R d -L-L-L-R e , or -O
  • one of R 5' and R 5" is selected from -O-L-R a -R e , -O-L-R a -R b -R e , -O-L-R a -R b -R a -R e , -O-L-R e , -O-L-R b -R e , -O-L-R b -R e , -O-L-R b -L-R a -R e , -O-L-R b -L-R b -R e , -O-R d -R e , -O-L-R b -R d -L-R e , -O-R d -L-R e , or -O-R d -L-R b -R e and the other one
  • one of R 5' and R 5" is selected from -O-L-R a -R e , -O-L-R a -R b -R e , -O-L-R a -R b -R a -R e , -O-L-R e , -O-L-R a -R e , -O-L-R b -R b -R e , -O-L-R b -R e , -O-L-R b -R e , -O-L-R b -L-R b -R e , -O-R d -R e , -O-L-R b -R d -L-R e , or -O-R d -L-R e and the other one of R 5 and R 5" , in particular R 5" , is -OH
  • one of R 5' and R 5" is selected from -O-L-R a -R b -R e , - O-L-R a -R b -R a -R e , -O-L-R e , -O-L-R a -R e , -O-L-R b -R b -R e , -O-L-R b -R e , -O-L-R b -L-R b ,R e , -O-R d -R e , -O-L-R b -R d -L-R e , or -O-R d -L-R e and the other one of R 5' and R 5" , in particular R 5" , is -OH or both R 5' and R 5" are independently from each other selected from -
  • one of R 5' and R 5" is selected from -O-L-R a -R b -R e , - O-L-R b -L-R b -R e , -O-R d -R e , -O-L-R b -R d- L-R e , -O-L-R a -R b -R a -R e , -O-L-R b -R b -R e , or -O-R d -L-R e and the other one of R 5' and R 5" , in particular R 5 , is -OH or both R 5' and R 5" are independently from each other selected from -O-L-R a -R b -R e , -O-L-R b -L-R b -R e , -O
  • one of R 5' and R 5" is selected from -O-L-R a -R b -R e , - O-L-R b -L-R b -R e , -O-R d -R e , or -O-L-R b -R d -L-R e and the other one of R 5' and R 5" , in particular R 5" , is -OH or both R 5' and R 5" are independently from each other selected from -O-L-R a -R b -R e , -O-L-R b -L-R b -R e , -O-R d -R e , or -O-L-R b -R d -L-R e , in particular one of R 5' and R 5" , in particular R 5' , is selected from -O-L-R a -R b -
  • one of R 5' and R 5" is selected from -O-L-R a -R e , -O-L-R b -L-R b -R e , or -O-R d -L-R b -R e and the other one of R 5' and R 5" , in particular R 5" , is -OH or both R 5' and R 5" are independently from each other selected from -O-L-R a -R e , -O-L-R b -L-R b -R e , or -O-R d -L-R b -R e , in particular one of R 5' and R 5" , in particular R 5' is selected from -O-L-R a -R e , -O-L-R b -L-R b -R e , or -O-R d
  • the compound is selected from:
  • the compound is selected from compound 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8, 9, 10a, 10b, 11a, 11 b, 12a, 12b, 22a, 22b, 23a, 23b, 24a, 24b, 25, 26a, 26b, 27, 28, 29.
  • the compound is selected from compound 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8, 9, 10a, 10b, 12a, 12b, 22a, 22b, 23a, 23b, 24a, 24b, 26a, 26b, 27, 28.
  • the compound is selected from compound 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8, 9, 10a, 10b, 12a, 12b, 23a, 23b, 24a, 24b, 26a, 26b, 27, 28.
  • the compound is selected from compound 7a, 7b, 8, 9, 10a, 10b, 12a, 12b, 23a, 23b, 24a, 24b, 26a, 26b, 27, 28.
  • the compound is selected from compound 7a, 7b, 8, 9, 10a, 10b, 12a, 12b, 23a, 23b, 26a, 26b, 27, 28.
  • the compound is selected from compound 7a, 7b, 8, 9, 10a, 10b, 12a, 12b, 26a, 26b, 27, 28.
  • the compound is selected from compound 10a, 10b, 12a, 12b, 26a, 26b,27.
  • the compound is selected from compound 10a, 10b, 12b, 26b, 27.
  • the compound is selected from 5a, 5b, 11a, 11b, 26a, 26b, 29.
  • the compound is selected from 5a, 5b, 11a, 26b, 29.
  • the compounds of the first aspect of the invention are provided for use in a method of treatment of disease.
  • a compound of the first aspect of the invention is provided for use in a method of treatment of infections, in particular bacterial infections, more particularly infections caused by
  • the compounds of the first aspect of the invention are used in a method of treatment of infections, in particular bacterial infections, more particularly infections caused by
  • the compounds of the compounds of the first aspect of the invention are used in a method of treatment of bacterial infections caused by drug resistant bacteria, in particular
  • the bacteria are gram + or gram - .
  • a dosage form for the prevention or treatment of bacterial infections comprising a compound according to one of the above aspects of the invention.
  • Dosage forms may be for enteral administration, such as nasal, buccal, rectal, transdermal or oral administration, or as an inhalation form or suppository.
  • parenteral administration may be used, such as subcutaneous, intravenous, intrahepatic or intramuscular injection forms.
  • a pharmaceutically acceptable carrier and/or excipient may be present.
  • the dosage form may comprise one fidaxomicin derivative according to the invention or several different fidaxomicin derivatives according to the invention ("cocktail"). If the dosage form is a cocktail, typically 2 to 10, in particular 2 to 4 different fidaxomicin derivatives are present.
  • Ultra high-performance liquid chromatography coupled to mass spectrometry UHPLC-MS: Ultimate 3000 LC instrument ( Thermo Fisher Scientific ) coupled to a triple quadrupole Quantum Ultra EMR MS ( Thermo Fisher Scientific ) using a reversed-phase column ( Kinetex ® EVO C18; 1.7 ⁇ m; 100 ⁇ , 50 x 2.1 mm; Phenomenex ) .
  • the LC was equipped with a HPG-3400RS pump, a WPS-3000TRS autosampler, a TCC-3000RS column oven and a Vanquish DAD detector (all Thermo Fisher Scientific ) .
  • High-performance liquid chromatography Prominence modular HPLC instrument ( Shimadzu ) coupled to a SPD-20A UV/Vis detector ( Shimadzu ) using a reversed-phase column ( Gemini-NX C18, 3 ⁇ m,10 ⁇ , 150 mm x 4.6 mm; Phenomenex ) for analytical HPLC and a reversed-phase column ( Gemini NX C18, 5 ⁇ m, 110 ⁇ , 250 mm x 21.2 mm; Phenomenex Synergi Hydro-RP, 10 ⁇ , 80 ⁇ , 250 mm x 21.2 mm; Phenomenex ) for preparative HPLC.
  • a reversed-phase column Gemini-NX C18, 3 ⁇ m,10 ⁇ , 150 mm x 4.6 mm; Phenomenex
  • a reversed-phase column Gemini NX C18, 5 ⁇ m, 110 ⁇ , 250 mm x 21.2 mm; Phenomenex Synergi Hydro-RP, 10 ⁇
  • the LC was equipped with a CBM-20A system controller, LC-20A solvent delivery unit, SIL-20A auto-sampler, CTO - 20A column oven, and DGU-20A online degassing unit (all Shimadzu ) .
  • the following solvents were used: H 2 O+0.1 % HCOOH (A), MeCN + 0.1 % HCOOH (B).
  • Specific optical rotation ⁇ D T Jasco P-2000 Polarimeter, measured at the indicated temperature T.
  • Infrared spectra SpectrumTwo FT-IR Spectrometer ( Perkin-Elmer ) equipped with a Specac Golden Gate TM ATR (attenuated total reflection) accessory; applied as neat samples or as films; 1/ ⁇ in cm- 1 .
  • fidaxomicin 100 mg, 0.0945 mmol, 1.0 eq.
  • K 2 CO 3 52.2 mg, 0.378 mmol, 4.0 eq.
  • lodoacetamide 22.7 mg, 0.123 mmol, 1.3 eq.
  • the reaction mixture was diluted with EtOAc (2.0 mL) and quenched with sat. aq. NH 4 Cl-solution (3.0 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3x).
  • reaction mixture was diluted with EtOAc (1.0 mL) and quenched with sat. aq. NH 4 Cl solution (1.0 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3x). The combined organic layers were washed with brine (2x), dried over MgSO 4 and the solvent was evaporated under reduced pressure. A mixture of mono-and disubstituted fidaxomicin- N , N -dimethylacetamide 6a and 6b was obtained.
  • disubstituted alloc-piperazine-fidaxomicin (15.4 mg, 0.0104 mmol, 1.0 eq.) was dissolved in dry DCM (1.0 mL) and 1,3-dimethylbarbituric acid (3.9 mg, 0.025 mmol, 2.4 eq.) was added.
  • the reaction mixture was cooled to 0 °C and tetrakis(triphenylphosphine)palladium (0.607 mg, 0. 52 ⁇ mol, 0.05 eq.) was added. The mixture was stirred at 0 °C for 1 h.
  • DCM 1.0 mL
  • water 2.0 mL
  • ciprofloxacin 250 mg, 0.754 mmol, 1.0 equiv.
  • dry THF 0.5 mL
  • Pyridine 61 ⁇ L, 60 mg, 0.754 mmol, 1.0 equiv.
  • bromoacetylbromide 65 ⁇ L, 152 mg, 0.754 mmol, 1.0 equiv.
  • the orange mixture was stirred at room temperature for 18 hours.
  • the product precipitated.
  • the yellow solid was filtered and washed with water (3 x 5 mL).
  • the filtrate was extracted with DCM (3 x 10 mL) and dried over MgSO 4 .
  • hexaethyleneglycol monomethyl ether (163 mg, 0.55 mmol, 1 eq.) was dissolved in THF (dry, 0.3 mL).
  • Triethylamine 150 ⁇ l, 112 mg, 1.10 mmol, 2 eq.
  • N , N -dimethylaminopyridine (16.3 mg, 0.133 mmol, 0.13 eq.) were added and the flask was cooled in an ice bath.
  • a solution of nosyl chloride (222 mg, 1.1 mmol, 1.8 eq.) in THF (1.0 mL) was added slowly by syringe.
  • reaction mixture was stirred at 0°C for five minutes and then allowed to warm to room temperature. After 18 hours of stirring at room temperature, the reaction mixture was filtered and the solid residue washed with THF (3 x 10 mL). The combined THF solutions were concentrated under reduced pressure. The oily residue was dissolved in DCM (15 mL) and washed with brine (15 mL). The aqueous phase was extracted with DCM (3 x 15 mL). The crude product was further purified by column chromatography (DCM/MeOH 96/4) to give the product as a yellow oil (239 mg, 0.50 mmol, 90 %). HRMS ESI(+) (MeOH) calculated for [M+H] + : 482.16906, found: 482.16923.
  • reaction mixture was stirred at 45 °C.
  • the reaction was monitored by analyzing aliquot samples by UHPLC-MS. After 2.5 hours, the reaction mixture was diluted with EtOAc (10 mL) and washed with ammonium chloride solution (15 mL). The aqueous phase was extracted with EtOAc (2x10 mL) and the combined organic phases were dried over magnesium sulfate. After filtration of the drying agent, the solvent was evaporated.
  • 2,6-Di-tert-butylpyridine (270 ⁇ l, 1.63 mmol, 20 eq.) and methyl iodide (25 ⁇ l, 0.4 mmol, 5 eq.) were added.
  • the reaction mixture was allowed to warm to room temperature. After 20 hours, the reaction mixture was worked up by filtering it over a pad of Celite and washing with DCM. This solution washed with ammonium chloride solution (2x10 ml) and brine (10 ml).
  • TBS(OTf) 90 ⁇ l, 104 mg, 0.39 mmol
  • 2,6-lutidine 87 ⁇ l, 80 mg, 0.75 mmol
  • dry DCM 0.6 ml
  • c 0.50 mmol/ml
  • reaction mixture was stirred for 20 min at room temperature and then heated to 35 °C. After 28 hours and after 2.5 days, another portion of Mel was added (40 ⁇ l, 91.2 mg, 20 eq., 40 ⁇ l, 91.2 mg, 20 eq.). After stirring for 3.5 days, the reaction mixture was worked up by filtering it over a pad of Celite and washing with DCM. The mixture was concentrated on the rotary evaporator, DCM was added (30 ml) and this solution washed with ammonium chloride solution (2x20 ml). The desired product was obtained as a colourless solid upon flash column (pentane/acetone 5/1) (20.7 mg, 0.02 mmol, 50 %; 75 % brsm). 21a: HRMS ESI+ (MeOH), calculated for [M+H] + : 1291.57649, found: 1291.57870.
  • 3-Azidopropan-1-ol was synthesized following a literature procedure: A. W. Gann, J. W. Amoroso, V. J. Einck, W. P. Rice, J. J. Chambers, N. A. Schnarr, Org. Lett. 2014, 16, 2003-2005 .
  • 3-bromopropan-1-ol (12.4 g, 89.2 mmol, 1 eq.) was dissolved in acetone (200 mL).
  • a solution of sodium azide (29.0 g, 466 mmol, 5.2 e.) in deionized water (120 mL) was added while stirring.
  • 3-Azidopropyl 4-nitrobenzenesulfonate was synthesized in analogy to a nosylation procedure reported in literature: J. Bucher, T. Wurm, K. S. Nalivela, M. Rudolph, F. Rominger, A. S. K. Hashmi, Angew. Chem. Int. Ed. 2014, 53, 3854-3858 .
  • 3-azidopropan-1-ol (2.50 g, 24.7 mmol, 1 eq.) was dissolved in THF (dry, 30 mL).
  • Fidaxomicin (101.4 mg, 95.8 ⁇ mol, 1 eq.) was weighed into a flame-dried 5 mL Schlenk tube under nitrogen atmosphere and dissolved in DMF (dry, 1 mL). 3-Azidopropyl 4-nitrobenzenesulfonate (40.9 mg, 143 ⁇ mol, 1.5 eq.) and K 2 CO 3 (60.8 mg, 0.44 mmol, 4 eq.) were added and washed down with more DMF (dry, 1 mL). The reaction mixture was stirred at 45 °C for 3 hours.
  • reaction mixture was diluted with EtOAc (10 mL), washed with a saturated aqueous solution of ammonium chloride (5 x 10 mL) and dried over MgSO 4 . After filtration of the drying agent, the solvent was evaporated to give a yellow oil.
  • reaction mixture was diluted with ethyl acetate (15 mL) and an aqueous solution of ammonium chloride (20 mL) was added.
  • the aqueous phase was extracted with ethyl acetate (15 mL) and the combined organic phases were washed with ammonium chloride solution (3x15 mL) and dried over magnesium sulfate. After filtration of the drying agent, the solvent was evaporated.
  • the dinuclear CuAAC catalyst (9.6 mg, 0.014 mmol) was weighed into an oven-dried Schlenk flask under an atmosphere of argon.
  • the crude mixture from the preceding reaction containing fidaxomicin as well as mono(azidopropyl)- and bis(azidopropyl)fidaxomicin was dissolved in DCM (2.0 mL) and added to the catalyst.
  • Glacial acetic acid 100 %, 11 ⁇ l, 12 mg, 0.19 mmol
  • 3-ethynylaniline 23 mg, 0.19 mmol; distilled prior to use at 110 °C oil bath temperature and 3 mbar
  • DCM 0.8 mL
  • the reaction mixture was diluted with DCM (dry, 10 mL), washed with brine (3 x 10 mL) and dried over MgSO 4 . The solvent was removed in vacuo.
  • the layers were separated and the aqueous phase extracted with diethyl ether (4 x 15 mL).
  • the organic phase was washed with ammonium chloride solution (2 x 50 mL).
  • the combined organic phases were dried over magnesium sulfate. After filtration of the drying agent, the solvent was evaporated.
  • 24a HRMS ESI+ (MeOH), calculated for [M+Na] + : 1251.41497, found: 1251.41380.
  • 24b HRMS ESI+ (MeOH), calculated for [M+NH 4] + : 1418.45790, found: 1418.45885.
  • 5-Propynylacetamide fluorescein was synthesized following a literature procedure.
  • 5-carboxyfluorescein (65.1 mg, 173.1 ⁇ mol, 1.0 equiv.) was dissolved in anhydrous DMF (2 mL, dry).
  • HOBt (46.2 mg, 341.3 ⁇ mol, 2.0 equiv.)
  • triethylamine (34.2 mg, 337.1 ⁇ mol, 1.9 equiv.) were added while stirring at room temperature.
  • N , N' -Diisopropylcarbodiimide (42.2 mg, 335.0 ⁇ mol, 1.9 equiv.) was added and the mixture was stirred for 20 minutes at room temperature.
  • 1-Nitroso-4-propargylpiperazine was synthesized following a literature procedure. [3] In a flame-dried 50 ml round-bottom flask, 1-nitrosopiperazine (1.53 g, 13.31 mmol) was dissolved in anhydrous MeCN (36 ml). Propargyl bromide (1.45 ml, 2.01 g, 13.52 mmol) and NEt 3 (3.70 ml, 26.62 mmol) were added and the reaction mixture was heated under reflux conditions for 5 hours. Reaction control after 5 h by TLC indicated only sluggish conversion.
  • 1-Amino-4-propargylpiperazine was synthesized following a literature procedure with a slightly different workup. [3] In a flame-dried 250 ml round-bottom flask, LiAlH 4 (228 mg, 6.0 mmol, 2.0 equiv.) was suspended in anhydrous Et 2 O (80 ml) and was stirred vigorously. A solution of 1-nitroso-4-propargylpiperazine (460 mg, 3.0 mmol, 1.0 equiv.) in anhydrous Et 2 O (20 ml) was added and the reaction mixture was stirred under reflux conditions for three hours.
  • O-(2-azidoethyl)heptaethylene glycol (215 mg, 0.545 mmol, 1.0 equiv.) was dissolved in DCM (dry, 2.0 mL).
  • Triethylamine 150 ⁇ L, 109 mg, 1.08 mmol, 2.0 equiv.
  • DMAP 15 mg, 0.13 mmol, 0.23 equiv.
  • Nosyl chloride (241 mg, 1.08 mmol, 2.0 equiv.) in DCM (1.0 mL) was added by syringe and washed down with more DCM (1.0 mL).
  • reaction mixture was stirred at 0 °C for five minutes and then allowed to warm to room temperature. After stirring at room temperature for 22 hours, the reaction mixture was poured on an aqueous solution of ammonium chloride (20 mL) and the phases were separated. The aqueous phase was extracted with DCM (3 x 15 mL). The combined organic phases were dried over magnesium sulfate.
  • the reaction mixture was stirred for 21.75 hours at 45 °C under an atmosphere of argon.
  • the reaction mixture was diluted with ethyl acetate (15 mL) and quenched with saturated ammonium chloride solution (15 mL).
  • the layers were separated and the aqueous phase extracted with ethyl acetate (2 x 15 mL).
  • the combined organic phases were dried over magnesium sulfate. After filtration of the drying agent, the solvent was evaporated.
  • the strains of Bacillus subtilis and Staphylococcus aureus were grown overnight at 37 °C on MH II agar plates.
  • BDTM BBLTM Mueller Hinton II Agar, BD Diagnostics The strains of Bacillus subtilis and Staphylococcus aureus were grown overnight at 37 °C on MH II agar plates.
  • MIC values were determined by broth dilution method according to the recommendations of the Clinical and Laboratory Standards Institute (CLSI; U.S.A.).
  • the inoculum size was about 7.5 x 10 5 colony forming units/well.
  • the compounds were diluted in H 2 O from 1.0 mg/mL stock solutions in methanol/H 2 O 1/1 in a 2-fold dilution series.
  • the microtiter plates were incubated at 37 °C overnight. Afterwards, the MIC (lowest concentration of the compounds with no bacterial growth observed) was determined by visual inspection.
  • MIC values were determined by visual inspection or by plate reader at 600 nm after 3-14 days (pre-tempered at 37°C with plastic foil, lid removed). Table 1: The MIC values in Table 1 are given in ⁇ g/mL and in nmol/mL.
  • a standard stock solution of each analyte in MeOH at a concentration of 1.0 mg/mL was prepared. All analytes were completely soluble in MeOH.
  • a standard stock solution of caffeine for use as internal standard (IS) in MeOH was prepared at a concentration of 1 mg/mL. These stock solutions were further diluted with MeOH to calibration standard samples at concentrations of 50, 100, 200, 300, 400, 500 ⁇ g/mL of analyte with each sample containing 50 ⁇ g/mL of caffeine as IS.

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996035702A1 (fr) * 1995-05-09 1996-11-14 Abbott Laboratories Composes de dialkyltiacumicine
WO2009070779A1 (fr) * 2007-11-27 2009-06-04 Optimer Pharmaceuticals, Inc. Composés macrocycliques antibiotiques et leurs procédés de fabrication et d'utilisation
WO2016004166A1 (fr) * 2014-07-02 2016-01-07 Xavier University Of Louisiana Stratégie de promédicament à base de bore pour une biodisponibilité augmentée et des besoins de dosage inférieur pour des molécules de médicament contenant au moins un groupe phénol (ou hydroxyle aromatique)

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Publication number Priority date Publication date Assignee Title
WO1996035702A1 (fr) * 1995-05-09 1996-11-14 Abbott Laboratories Composes de dialkyltiacumicine
WO2009070779A1 (fr) * 2007-11-27 2009-06-04 Optimer Pharmaceuticals, Inc. Composés macrocycliques antibiotiques et leurs procédés de fabrication et d'utilisation
WO2016004166A1 (fr) * 2014-07-02 2016-01-07 Xavier University Of Louisiana Stratégie de promédicament à base de bore pour une biodisponibilité augmentée et des besoins de dosage inférieur pour des molécules de médicament contenant au moins un groupe phénol (ou hydroxyle aromatique)

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A. W. GANN; J. W. AMOROSO; V. J. EINCK; W. P. RICE; J. J. CHAMBERS; N. A. SCHNARR, ORG. LETT., vol. 16, 2014, pages 2003 - 2005
ELIAS KAUFMANN ET AL: "Total Synthesis of the Glycosylated Macrolide Antibiotic Fidaxomicin", ORGANIC LETTERS, vol. 17, no. 14, 17 July 2015 (2015-07-17), pages 3514 - 3517, XP055485827, DOI: 10.1021/acs.orglett.5b01602 *
G. R. FULMER; A. J. M. MILLER; N. H. SHERDEN; H. E. GOTTLIEB; A. NUDELMAN; B. M. STOLTZ; J. E. BERCAW; K. I. GOLDBERG, ORGANOMETALLICS, vol. 29, 2010, pages 2176 - 2179
J. BUCHER; T. WURM; K. S. NALIVELA; M. RUDOLPH; F. ROMINGER; A. S. K. HASHMI, ANGEW. CHEM. INT. ED., vol. 53, 2014, pages 3854 - 3858
K. PENUELAS-URQUIDES; L. VILLARREAL-TREVINO; B. SILVA-RAMIREZ; L. RIVADENEYRA-ESPINOZA; S. SAID-FERNANDEZ; M. B. DE LEON, BRAZ, J. MICROBIOL., vol. 44, 2013, pages 287 - 290
M. A. BRUN; K.-T. TAN; R. GRISS; A. KIELKOWSKA; L. REYMOND; K. JOHNSSON, J. AM. CHEM. SOC., vol. 134, 2012, pages 7676 - 7678
REVILL P ET AL: "Tiacumicin B", vol. 31, no. 6, 31 December 2006 (2006-12-31), pages 494 - 497, XP002696172, ISSN: 0377-8282, Retrieved from the Internet <URL:http://journals.prous.com/journals/servlet/xmlxsl/dof/20063106/pdf/df310494.pdf?p_JournalId=2&p_refId=1000709&p_IsPs=N> [retrieved on 20130425], DOI: 10.1358/DOF.2006.031.06.1000709 *
S. A. COCHRANE; X. LI; S. HE; M. YU; M. WU; J. C. VEDERAS, J. MED. CHEM., vol. 58, 2015, pages 9779 - 9785

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